using various substituted aryl triflates8 failed to give ap-
preciable quantities of thioether 2 with our substrate (1).
However, this reaction occurred readily upon heating for 20
min at 150 °C in a microwave reactor. The commercially
available aryl bromide could also be employed in place of
1, but the yields were consistently lower (24-44%) under
comparable reaction conditions. ONB-thiol failed to provide
access to ONB-protected thiophenol under our optimized
microwave conditions, and the S-trityl protecting group was
not investigated at this stage as it was unlikely to survive
the subsequent reaction conditions. Following Vilsmeier
formylation,4f aldehyde 3 was conjugated directly to glycine
using H-Gly-OtBu (utilizing the tert-butyl ester to ease
purification of the product) via reductive amination employ-
ing sodium triacetoxyborohydride as reductant in excellent
yield.9 The auxiliary-glycine conjugate 4 was then prepared
for standard SPPS via TFA-mediated cleavage of the tert-
butyl ester followed by Fmoc protection of the secondary
amine. Synthesis of protected 1-(2,4-dimethoxyphenyl)-2-
mercaptoethyl auxiliaries 9 and 10 was completed in only
two steps. PMB- and trityl-protected thiol moieties were
introduced by the action of the corresponding thiols on
commercially available bromoacetophenone 6 to afford
thioethers 7 and 8 in excellent yields. Glycine was then
introduced via reductive amination using sodium cyanoboro-
hydride as a reductant in refluxing methanol.10 This route
was investigated since under identical conditions for the
preparation of 4 (H2NCH2CO2tBu, Na(AcO)3BH, AcOH/
DCM), only reduction of the ketone was observed. Further-
more, only the glycine-linked auxiliary 4 was amenable to
the tert-butyl deprotection and Fmoc protection cycle (9 was
resistant to Fmoc protection). We reasoned that, if the
increased steric bulk proximal to the amino group of 9 was
precluding Fmoc protection, then Fmoc protection might not
be required at all during peptide synthesis. Consequently, 5
and 9 or 10 were introduced directly (using 3-5 equiv) to
preassembled peptides corresponding to selected GlyCAM-1
protein fragments (Table 1) with no evidence of multiply
coupled species arising from the use of 9 in SPPS. Interest-
ingly, auxiliaries 11 and 12 of the type commonly employed
in the submonomer approach (through subsequent reaction
with bromoacylated peptides)4 could also be conveniently
prepared under identical reaction conditions employing
ammonium acetate in place of glycine in the reductive
amination. After Fmoc deprotection and cleavage from the
resin of 5-linked peptide 13 (Table 1), the PMB protecting
group was efficiently removed using excess Hg(OAc)2 in
10% aqueous AcOH followed by the addition of DTT to a
final concentration of 5% w/v. 9-linked peptides (14 and 15)
were more resistant to such treatment, but the SPMB group
was readily cleaved upon exposure to Hg(OAc)2 in neat TFA
for 10 min at 0 °C followed by dilution to 10% aqueous
Scheme 1. Strategy for Introduction of Glycine-Linked
4,5,6-Trimethoxy-2-mercaptobenzyl and
1-(2,4-Dimethoxyphenyl)-2-mercaptoethyl Auxiliary Cassettes
(Trt) since reaction conditions employed for their removal
have been shown to be compatible with glycopeptide
synthesis.4g,5,6 For the synthesis of glycine-linked 4,5,6-
trimethoxy-2-mercaptobenzyl auxiliary 5 (Scheme 2), we
Scheme 2. Synthesis of Auxiliary-Linked Glycine Cassettes
introduced the SPMB-protected thiophenolic moiety using
triflate 1 and PMB-thiol in a single step using the palladium-
catalyzed coupling chemistry developed by Buchwald and
Hartwig.7
Initially, we were disappointed to find that reported
conditions for palladium-catalyzed aryl C-S bond formation
(6) (a) Marcaurelle, L. A.; Bertozzi, C. R. J. Am. Chem. Soc. 2001, 123,
1587. (b) Nicolaou, K. C.; Watanabe, N.; Li, J.; Pastor, J.; Winssinger, N.
Angew. Chem., Int. Ed. 1998, 37, 1559.
(7) (a)Murata, M.; Buchwald, S. L. Tetrahedron 2004, 60, 7397. (b)
Wolfe, J. P.; Buchwald, S. L. J. Org. Chem. 2000, 65, 1144. (c) Wolfe, J.
P.; Buchwald, S. L. J. Org. Chem. 1997, 62, 1264. (d) Marcoux, J.-F.;
Wagaw, S.; Buchwald, S. L. J. Org. Chem. 1997, 62, 1568. (e) Mann, G.;
Baranano, D.; Hartwig, J. F.; Rheingold, A. L.; Guzei, I. A. J. Am. Chem.
Soc. 1998, 120, 9205.
(8) Zheng, N.; McWilliams, J. C.; Fleitz, F. J.; Armstrong, J. D., III;
Volante, R. P. J. Org. Chem. 1998, 63, 9606.
(9) H2N-Ala-OtBu was also introduced under identical conditions in 96%
yield.
(10) Williams, R. E.; Ehrlich, P. P.; Zhai, W.; Hendrix, J. J. Org. Chem.
1987, 52, 2615.
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Org. Lett., Vol. 6, No. 25, 2004